How to manage ADHD in a patient with anxiety and depression who doesn't tolerate stimulants and can't access atomoxetine?

Managing ADHD Without Atomoxetine in Patients with Anxiety and Depression Who Cannot Tolerate Stimulants

When atomoxetine is unavailable and stimulants are not tolerated, initiate bupropion as the primary pharmacological option while simultaneously starting an SSRI (fluoxetine or sertraline) to address the comorbid anxiety and depression. 1

Primary Medication Strategy

Bupropion as First-Line Non-Stimulant Alternative

• Start bupropion SR at 100-150 mg daily or XL at 150 mg daily, titrating to maintenance doses of 100-150 mg twice daily (SR) or 150-300 mg daily (XL), with a maximum of 450 mg per day. 1
• Bupropion is explicitly positioned as a second-line agent for ADHD when stimulants have failed or caused intolerable side effects, with evidence showing decreased ADHD symptom severity compared to placebo. 1
• Unlike atomoxetine, bupropion does not cause somnolence and fatigue as primary adverse effects, making it more suitable when energy and motivation are concerns. 1
• Bupropion works more rapidly than atomoxetine (which requires 6-12 weeks for full effect), though still requires weeks to months for full therapeutic benefit. 1, 2

Critical Safety Considerations with Bupropion

• Monitor closely for worsening hyperactivity, insomnia, anxiety, and agitation during the first 2-4 weeks, as bupropion is inherently activating. 1
• Be especially cautious in patients with comorbid anxiety disorders, as bupropion's activating properties can initially worsen anxiety symptoms. 1
• The combination of bupropion with SSRIs is well-established, with lower discontinuation rates due to adverse events compared to other augmentation strategies. 1
• Never use bupropion concurrently with MAO inhibitors due to risk of hypertensive crisis; ensure at least 14 days elapse between discontinuation of an MAOI and initiation of bupropion. 1

Addressing Comorbid Anxiety and Depression

SSRI Selection and Initiation

• Add an SSRI (fluoxetine 20-40 mg daily or sertraline 25-50 mg daily) to the bupropion regimen, as no single antidepressant effectively treats both ADHD and depression. 1, 3
• SSRIs remain the treatment of choice for depression and anxiety, are weight-neutral with long-term use, and can be safely combined with bupropion. 1
• Escitalopram and citalopram have the least effect on CYP450 enzymes and lowest drug interaction propensity, making them alternative SSRI choices. 3
• Start SSRIs at low doses and titrate slowly, monitoring especially in the first 24-48 hours after dosage changes for serotonin syndrome risk. 3

Monitoring for SSRI Therapy

• Screen for suicidality, clinical worsening, and unusual behavioral changes, particularly during the first few months or at dose changes. 1, 3
• Assess for initial SSRI-induced anxiety or agitation, which typically emerges in the first 1-2 weeks and usually resolves with continued treatment. 2
• SSRIs require 3-4 weeks to reach full therapeutic effect, so allow adequate time before adjusting doses. 2

Alternative Non-Stimulant Options

Alpha-2 Agonists as Adjunctive or Alternative Therapy

• Consider guanfacine extended-release (1-4 mg daily) or clonidine as alternatives, particularly when sleep disturbances, tics, or emotional dysregulation are prominent. 1, 3
• These agents treat both ADHD symptoms and emotional dysregulation, with guanfacine having higher specificity for alpha-2A receptors resulting in less sedation than clonidine. 1
• Alpha-2 agonists require 2-4 weeks for full effect and are FDA-approved as monotherapy or adjunctive therapy for ADHD. 1
• Administer in the evening due to somnolence/fatigue as an adverse effect, which can actually benefit patients with sleep disturbances. 1
• Never abruptly discontinue alpha-2 agonists; taper by 1mg every 3-7 days to avoid rebound hypertension. 1

Tricyclic Antidepressants (Use with Extreme Caution)

• Tricyclic antidepressants are considered second-line agents at best for ADHD treatment due to their greater lethal potential in overdose. 1
• TCAs are superior to placebo in treating ADHD but are limited by side effects including sedation, dry mouth, and constipation. 4
• Given the comorbid depression and anxiety, TCAs carry increased risk and should generally be avoided in favor of safer alternatives. 1

Treatment Algorithm

Step 1: Initial Medication Regimen

• Start bupropion SR 100-150 mg daily in the morning. 1
• Simultaneously initiate an SSRI (fluoxetine 20 mg or sertraline 25-50 mg daily). 1, 3
• Monitor blood pressure and pulse at baseline and regularly during treatment. 1

Step 2: Titration Phase (Weeks 2-8)

• Increase bupropion to 100-150 mg twice daily (SR) or 150-300 mg daily (XL) based on ADHD symptom response and tolerability. 1
• Titrate SSRI at 1-2 week intervals for shorter half-life agents (sertraline) or 3-4 week intervals for longer half-life agents (fluoxetine). 2
• Use standardized symptom rating scales to systematically assess treatment response for both ADHD and mood/anxiety symptoms. 2

Step 3: Reassessment at 8-12 Weeks

• If ADHD symptoms remain inadequately controlled despite optimized bupropion dosing, add guanfacine extended-release 1 mg daily in the evening. 1, 3
• If anxiety remains problematic despite adequate SSRI dosing, add cognitive behavioral therapy (CBT) to the medication regimen, as combination treatment shows superior outcomes. 2
• Titrate guanfacine by 1 mg weekly based on response and tolerability, up to maximum 7 mg/day. 1

Step 4: Long-Term Management

• Continue monitoring for suicidality, particularly given the comorbid depression and anxiety. 1, 3
• Track height and weight at each visit if applicable. 1
• Implement psychosocial interventions including psychoeducation and behavioral therapy as adjuncts to medication. 1

Common Pitfalls to Avoid

• Do not assume bupropion alone will effectively treat both ADHD and depression; always add an SSRI for mood symptoms. 1
• Do not use bupropion as monotherapy in patients with prominent anxiety without careful monitoring, as it can exacerbate anxiety initially. 1
• Do not combine bupropion with MAO inhibitors or prescribe benzodiazepines for anxiety in ADHD patients, as benzodiazepines may reduce self-control and have disinhibiting effects. 1
• Do not expect rapid ADHD symptom improvement with bupropion; it requires weeks to months for full effect, unlike stimulants which work within days. 1, 2
• Do not abruptly discontinue SSRIs or alpha-2 agonists; always taper to prevent discontinuation syndrome or rebound hypertension. 1, 3

Essential Psychotherapy Integration

• Cognitive Behavioral Therapy (CBT) specifically developed for ADHD is the most extensively studied psychotherapy and has increased effectiveness when combined with medication. 1
• Mindfulness-Based Cognitive Therapy (MBCT) and Mindfulness-Based Stress Reduction (MBSR) help most profoundly with inattention symptoms, emotion regulation, executive function, and quality of life. 1
• Behavioral interventions can enhance medication effects and allow for lower medication doses, potentially reducing adverse effects. 2